In 1975 Tait isolated two catecholamide siderophores from Paracoccus dentrificans [Tait, G. H. Biochem., 146, p. 191 (1975)], namely, N.sup.1, N.sup.8 -bis(2,3-dihydroxybenzoyl)spermidine (compound II) and N.sup.4 -[N-2-hydroxybenzoyl)-L-threonyl]-N.sup.1,N.sup.8 -bis(2,3-dihydroxybenzoyl)spermidine (compound III) in FIG. 2. It was demonstrated that the former catecholamide is a biochemical precursor of the latter. Shortly after the isolation and identification of these iron sequestering agents, Jacobs and Tait [Jacobs et al, Biochem. Biophys. Res. Commun., 74, p. 1626 (1977)] demonstrated the potential of these catecholamides as therapeutic agents for the treatment of various iron overload syndromes, e.g., Cooley's anemia [Jacobs, A., Br. J. Haematol., 43, p. 1 (1979); Martell et al, Eds. "Development of Iron Chelators for Clinical Use"; Elsevier, North Holland, Inc., New York, 1981]. Compound II, a tetradentate ligand, removed iron from transferrin, one of the body's iron binding proteins, substantially better than compound III, a potentially hexacoordinate ligand. Furthermore, both of these catecholamides were more effective at removing iron from this iron shuttle protein than was desferrioximine, the clinical device currently used in chelation therapy. Unfortunately, because compounds II and III were only obtainable in milligram quantities from bacteria, a complete biological evaluation was not possible. However, these findings did generate interest in this new family of siderophores. Following Tait's discovery, a number of model catecholamide siderophores were synthesized and their binding stoichiometries as well as the thermodynamics of iron binding were evaluated: [Weitl et al, J. Am. Chem. Soc., 101, p. 2728 (1979); Carrano et al, J. Am. Chem. Soc., 101, p. 5401 (1979); Harris et al, J. Am. Chem. Soc., 101, p. 6534 (1979); Weitl et al, J. Am. Chem. Soc. 102, p. 2289 (1980); Weitl et al, J. Org. Chem., 46, p. 5234 (1981)]. However, neither compound II or III was actually synthesized until recently [Peterson et al, Tetrahedron Lett. 4805 (1979); Bergeron et al, J. Org. Chem., 45, p. 1589 (1980); Bergeron et al, J. Med. Chem., 23, p. 1130 (1980)].
It is peculiar, however, that nature should produce a structurally more complicated, less effective iron chelator (III) from a less complicated, more effective chelator (II). However, Peterson et al [Tetrahedron Lett., 4805 (1979); and Peterson et al, J. Am. Chem. Soc., 102, p. 7715 (1980)] demonstrated that this seeming inefficiency could be explained by reconsidering Tait's original proof of structure for compound III. They demonstrated that the group fixed to the central nitrogen of the sperimidine backbone was not an N-2-hydroxybenzoyl-L-threonyl moiety but rather a 2-hydroxyphenyl-4-carboxyl-5-methyl-2-oxazoline, i.e., compound I of FIG. 3, and that this oxazoline ring was opened to the threonyl compound under the acidic conditions of Tait's isolation procedure. In the oxazoline or closed form, compound I represents a hexacoordinate Fe (III) binding ligand which, in fact, binds Fe (III) tighter than either compound II or compound III.
Synthesis of compound II and analogs thereof have previously been suggested. See [Bergeron et al, J. Org. Chem. 45, p. 1589 (1980); Bergeron et al, J. Med. Chem., 23, p. 1130 (1980); Bergeron et al, J. Org. Chem., 18, p. 3712 (1981); and Bergeron et al, J. Org. Chem., 46, p. 4524 (1981)]. These catecholamides have been shown to be potent iron chelators, and effective for removing iron from iron overloaded animals.
It is an object of the present invention to provide a method for the synthesis of the compounds represented by formula (I).